Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)- 1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity

Nozomi Saito, Yoshitomo Suhara, Masaaki Kurihara, Toshie Fujishima, Shinobu Honzawa, Hitoshi Takayanagi, Toshiro Kozono, Masahiko Matsumoto, Masayuki Ohmori, Naoki Miyata, Hiroaki Takayama, Atsushi Kittaka

研究成果: Article査読

70 被引用数 (Scopus)

抄録

A concise and efficient synthetic approach to 2α-(ω- hydroxyalkoxy)-1α,25-dihydroxyvitamin D3 (4a-c), including 2-epi-ED-71, was developed starting from D-glucose as a chiral template for the construction of the 2α-modified A-ring precursors (11a-c). It was found that the best ligand for the bovine thymus vitamin D receptor (VDR) in this series is 4b, which has 1.8 times greater binding affinity for the bovine thymus VDR than that of the natural hormone 1. Interestingly, potency in the induction of HL-60 cell differentiation for 4a-c was almost the same or weaker than that of 1 despite the strong binding affinity for the VDR. Next, we were interested in the "double modification" of 1 based on 4a-c with C20-epimerization, affording 2α-(ω-hydroxyalkoxy)-20-epi-1α, 25-dihydroxyvitamin D3 (20-epi-4a-c). All three 2α-substituted 20-epi analogues of 1 (20-epi-4a-c) exhibited stronger binding affinities for the VDR, and their conformations in the ligand binding domain of VDR were analyzed by molecular modeling. Double-modified analogues of 20-epi-4a-c showed marked HL-60 cell differentiation activity, and 20-epi-4a possesses an activity 58-fold higher than that of the natural hormone 1.

本文言語English
ページ(範囲)7463-7471
ページ数9
ジャーナルJournal of Organic Chemistry
69
22
DOI
出版ステータスPublished - 2004 10月 29
外部発表はい

ASJC Scopus subject areas

  • 有機化学

フィンガープリント

「Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)- 1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル